Folding@Home Contribution

Since the commencement of this project on February 6th, 2008, our team has contributed 195 work units to the FAH endeavor. While this is a seemingly insignificant amount compared to some other teams that have continuous CPU time devoted to this, every contribution helps. It is the combination of all of the contributions by users that makes this project feasible. We hope to continue to use this project as long as grid-computing is still an option.

Heritability in Cancer

Recently we have looked into the role of heritability in cancers. There have been many studies looking into to this and most have returned similar results. One study done by Kari Hemminki and colleagues found that genetic heritability contributed anywhere from 10-14% in the cancers studied. Another study by Paul Lichtenstein also concluded that inherited genetic factors make a minor contribution to the susceptibility of most neoplasms. This indicates that the environment has the principal role in causing sporadic cancer. Based on these studies I would estimate that the heritability factor of cancer is fairly low. Also because it is so low, selection would not have a major influence on the disease as there is not much to select for. Similarly the effects of inbreeding would also be minimal. However, in certain cases where inheritance does play a role, inbreeding could increase the probability of passing those genes on as it would also increase there exposure to selection.

Reflection (Steve)

This project has also taught me a lot about the practical applications of evolution. Until this class and mainly this project I never thought about evolution being relevant to things such as disease today. Through the papers I also learned a lot about the p53 gene and cancer in general. I was completely unaware of the p53 gene family before reading these papers. Similar to the other members of my group I did not know that there was such a complex family of genes that regulated cell apotosis. I thought that there were simply environmental triggers that caused a certain cell to begin the process of cell death. Another thing that was surprising to me was how genetically predisposed some can be to cancer. I always knew that there was some hereditary effect, but I thought that for the most part the majority of cancer cases were due to mutations caused mainly by genetic error or environmental influences. This project has been enlightening in many ways and has been a worthwhile experience.

Why doctors need to know about evolution

For us, there is one reason that stands out above the others as to why doctors need to have a working knowledge of evolution. We feel that a very big problem in the medical field today is bacterial resistence to drugs. If a doctor does not know about evolution, he or she could easily prescribe antibiotics to every patient that shows symptoms of a bacterial infection. Presumably, these doctors would prescribe the same drug repeatedly to every patient they encounter. The reason that this is a problem is that bacteria can build resistence to drugs that are over prescribed. As we learned in evolution class, the antibiotics will put a pressure on the bacteria. Only the bacteria that, by random chance, have the ability to withstand the antibiotic, will survive and reproduce. The selection for these resistant bacteria will allow them to thrive while the bacteria which are not resistant will fall victim to the drugs. As all of the non-resistant bacteria are eliminated, only the resistant ones will remain, leading to a completely resistant strain of bacteria.

A perfect example of this kind of selection leading to resistant bacteria is with Staphylococcus aureus. The over-prescription and misuse of the antibiotic Vancomycin has led to a resistant strain of S. aureus. If doctors have a working knowledge of evolution, they will understand that the selective pressure on bacteria from antibiotics will lead to such a situation. With this knowledge, they will hopefully restrain the use of antibiotics to the cases that absolutely need them, or at least use a variety of antibiotics. It is also important that doctors know about evolution like this so they can better inform their patients about the importance of following the regimen for antibiotic use. If a patient stops using the prescribed drug too soon, only the strongest bacteria will be left and able to multiply. Because of Vancomycin-resistant Staphylococcus aureus and other drug-resistant bacteria, we feel that doctors must understand both the mechanisms and effects of evolution.

What I have learned from this project thus far (Rick)

This project has taught me quite a bit so far about a practical use of evolution. While many are discussed in class, having to research a topic that relates to diseases that people we know have helps me to put my classroom knowledge to more use. From the papers I read for this project about p53 mutations and how that affects cancer, I have learned several things. First of all, I have never learned about the moleuclar nature of cancer before reading these articles. Just like Connor, I always thought cancer just happened when cells were not able to undergo apoptosis. Through reading about p53, I have learned that gene duplication, and subsequent mutations on the duplicated genes, allows for the creation of a gene family. When all of the genes in the gene family are selected for in such a way that they work together in harmony, it is necessary that all are expressed perfectly to allow the cells to function properly. In the case of p53, mutations and misfoldings cause at least one of the genes in the p53 gene family to not function properly which prevents apoptosis. For me, learning that mutations like this inhibit apoptosis gives me a small understanding of what can cause cancer. Studying the evolution that allows the genes in the gene family to arise through gene duplication has allowed me to fully understand exactly what happens. This kind of supporting knowledge allows me to have a better grasp on p53 and its ability to promote cancer. I have thoroughly enjoyed having the opportunity to build my knowledge of this protein family while putting my evolution knowledge to practical use.

What I learned (Connor)

I learned from the papers about how much evolution can affect cancer. I learned how much of an effect p53 has on whether cancer will develop to a stage that is terminal or not, and I also learned that p53 can determine whether an individual will even develop cancer at all. I learned that cancer is regulated to some extent by a gene (p53) and until now I had never known that there was a gene responsible for preventing the uncontrollable duplication of cells. I thought that cancer was as simple as a cell being unable to stop duplicating itself, but now I have an appreciation for the fact that it is a much more complicated phenomenon and this fact makes me realize that cancer is even more dangerous than I had previously thought. This seems to explain to me why a cure for it has eluded the hard working scientific community for so many years.

March 26th Questions (p53)

1. Regulatory genes are those genes which control the transcription of other regulatory genes or structural genes. The method of this control can happen in a variety of ways including activating, suppressing, or enhancing the transcription of the structural genes. Structural genes are those that code for proteins that are expressed as part of the individual’s phenotype. Regulatory genes often control the expression of more than just one structural gene; also, because the regulatory genes can code for other regulatory genes, a cascade effect is created. The initial regulatory genes control many other genes down the chain. Thus, if there is a mutation in the DNA sequence of the regulatory gene, many subsequent genes will be affected.

The p53 gene is a regulatory gene. Specifically, it is a transcription factor that is activated when the cell experiences abnormal levels of stress. There are nine isoforms of this genes that work together to cause transcription genes to be activated. In the case of the p53 gene, activated transcription genes lead to a target cell beginning the process of apoptosis, or cellular suicide. If the first gene in this pathway (the transcription gene p53) is not allowed to do its job, then none of the subsequent genes in the cascade will be affected, and the overall result of apoptosis will not be achieved. This regulatory gene cascade is present in many genes other than p53. In all of these genes, inhibition of the first effecter prevents any other effects from being expressed. When the p53 gene is inhibited, the genes causing apoptosis are not expressed, thus the cell does not die and a tumor forms. Because there are nine isoforms that play a role in this activation, each of these must be expressed in a specific manner for the p53 gene to be fully functional, and if any of these isoforms is not expressed correctly, this can lead to tumor formation (Bourdon, 280). It is important, then, to study not only the p53 protein as a whole for cancer research, but more specifically how the expression of each of the isoforms is controlled as well as what misfoldings can cause errors.


2. In an evolutionary sense, why is it informative to study cancer and its implications in mice (see Lee and Bernstein, 1993 and Bourdon, 2007)?

Because we have learned that all diseases, cancer included, are subject to mutation, which could prove them even more deadly to all organisms across the world. At the same time all organisms may experience mutations in any part of their body that could potentially grant that organism immunity to a specific disease, virus, or specific kind of cancer. Through studying cancer’s implications in mice, it might be possible to draw helpful parallels from how mice evolve in response to the cancer and how the cancer evolves in response to the mice. These implications would be especially helpful if a mutation in hox/ regulatory genes yields immunity to a certain kind of cancer. This is important because that gene could be selected for and eventually become more abundant in mice populations on its own, but scientists could observe the properties of that mutation and work on researching a way to achieve the same properties in human regulatory genes, so that we may be closer to a cure for certain kinds of cancer.

Another reason that studying cancer and its implications in mice is beneficial is that there are fewer ethical issues associated with mice. In humans, cancer cells cannot be implanted to watch how the genes are expressed throughout the disease progression. In mice, however, this is a possibility. Furthermore, this can be done with many mice which allows researchers to identify if there is more than one misfolding that causes irregular expression of the p53 gene or any of its isoforms. Mice are preferable to any other animal for diseases such as this because their physiology is closely related to that of humans. The way the disease progresses and the mice’s response to drugs will closely parallel the response in humans. Thus, any discoveries that arise in the lab with the mice can be more easily transitioned into a human context.


3. Bourdon discusses the sequence similarity in portions of p53, p63 and p73, and refers to them as a gene family. How do you think these genes arose? Are they paralogs or orthologs of one another? By what mechanism might they have gained new functions?

A gene family is one in which the genes share a known homolog and they also tend to be biochemically similar. The p53, p63, and p73 genes all have a high level of sequence similarity in the DNA-binding domain. This allows the p63 and p73 to transactivate p53-responsive genes causing cell-cycle arrest and ultimately apoptosis. There have also been studies showing that the p53 gene family has a dual gene structure found in Drosophila, zebrafish, and humans. It has also been shown that the human p53 gene has a dual gene structure similar to p73 and p63 genes(Bourdon 277). Due to the similarity in structure and sequence between both p53 genes in other species as well as the similarity between p53 genes and p63 and p73 genes within the same species it is likely that this gene family arose a result of duplication. Gene duplication happens when there is an error in mitosis leading to the duplication of certain gene sequence. These duplications can then grow larger and replicate again through subsequent cell division, which is likely the case with the p53 gene family. If this is the case, these genes are likely paralogs that resulted from a gene duplication event. This is when a gene in an organism is duplicated to occupy two different positions in the same genome. However, as Bourdon mentions, the members of the p53 gene family all have different biological functions. If they all originated from the same duplicated sequence one may wonder how this could be. The duplicated gene sequences, once a part of the genome, are free to mutate and gain new function just as any other gene. Also, if one sequence mutates it will not necessarily affect the others. If the mutation to one of these paralogs is advantageous it may be selected for and become more abundant in the population. It is likely that the p53 gene family originated in a manner similar to this.


4. In the Bourdon paper, the author discusses how changes in expression of the 9 different p53 isoforms (proteins) can cause “genome instability, cancer and other pathologies.” Why then is it important to study protein folding and misfolding in these isoforms?

As we mentioned before, the nine isoforms need to be expressed in a specific manner to allow a stressed cell to enter apoptosis. If any of these isoforms are expressed in an inappropriate amount, the transcription of structural genes that initiate apoptosis will not occur and tumor formation can result. It is important, then, to study these folding and misfoldings to isolate the specific causes of misexpression of the isoforms of p53. If the folding program can predict which misfoldings will lead to the most prevalent mutation that causes the isoforms to lose functionality, then appropriate treatments that prevent or target these misfoldings can be researched. Attacking a cancer that is promoted by a protein, but not knowing any of the properties of this protein can be a fruitless fight. If researchers can determine exactly how the mutation occurs, then a treatment that prevents this mutation could possibly be created. In addition, if this mutation has already occurred in a person, perhaps a treatment could be developed that eradicates this specific protein from the body and other treatment could allow the protein to be folded correctly and prevent tumor formation. In our opinion, these treatments are quite possible in the future if the exact cause of the misfolding is pinpointed through programs such as Folding@Home.


5. Typically, p53 is a “tumor-suppressor gene,” which indicates that if it loses function, tumors will result. However, expression of some of the isoforms of p53 can actually contribute to tumor formation. Further, not all mutations in p53 result in a loss of function. This makes it difficult to understand the clinical role of p53. Considering people like Debbie, why is it so vital to determine the status of p53 in each patient?

It is so vital to determine that status of p53 in each patient because the expression of p53 isoforms can drastically change how cancer behaves and develops. At the same time, knowing the status of p53 in each patient could lend helpful insight that could show a growth that was originally thought to be cancerous, is actually not, since certain types of p53 genes will suppress cancerous tumors. In the case of Debbie, the doctors were not 100% positive that the tumor was cancerous until they had performed an operation, so it is in a case exactly like that in which determining the status of the p53 gene would be vital. With so many isoforms contributing to a variety of different functions, behaviors, and characteristics, knowledge on a patient to patient basis will always serve helpful in treating each patient to the fullest potential of our twenty first century biological and technological advances.

Interview

The service-learning project our group deicded to work on is cancer. Because of this, we felt that exploring how cancer affects the patient would bring more of a personal light to the disease. Knowing that there are people with families and feelings behind all of the statistics that are so often quoted makes one realize the importance of contributing to help find a cure. We decided to contact a relative of one person in our group who found out that she had an early stage ovarian tumor. The person's name is Debbie, and she was very cooperative with our request because she agreed that people will be more likely to help find a cure if they realize that it can hit close to home. The transcript of our interview is posted below:

Group: How did you find out you had cancer?

Debbie: I moved from Chicago to Bolivar, MO last year, and both my husband and I found new doctors and had routine checkups. My new doctor asked me if I had a papsmear recently, and I had not since I lived in Chicago. The doctor did his own testing, and when he called me on the phone he explained to me that he detected an small tumor. He wanted to perform an ultrasound. He did so the next Tuesday. He called me on Wednesday and indicated that the tumor may or may not be cancerous, but would have to perform immediate surgery in order to find out.
I told my doctor I had numbness in my back and often experienced lower back discomfort especially while lying in bed and getting out of bed.



Group: Was finding out that you had cancer difficult?

Debbie: Yes. My doctor referred me to a gynecologist. I made an appointment with my oncologist/gynecologist. He conducted a pelvic exam. I was very anxious to find out about what kind of treatments I would undergo and if the cancer would be terminal or not.



Group: After finding out about your cancer, did you experience any lifestyle changes?

Debbie: I did not experience any particular lifestyle changes. I feel that did have some mental changes, more specifically being appreciative of having found the cancer so early, because it would have surely been terminal if I didn't. When I had a checkup with my doctor before going back to work, there was a lady who had a terminal cancer sitting in front of me. I could feel her emotional pain and it made me even more grateful that I could continue my life normally after the treatments.



Group: How did your cancer affect your family?

Debbie: In my family many people were there to support me and they came to see me when I was in the hospital. My husband was affected just as much as I was because he had to be there for me and go with me during my treatments.



Group: How did it change the way you view life?

Debbie: Things don’t bother me as much as before. I feel that having experienced such a serious event caused me to realize what is important in life and not to make a big deal out of the small things.



Group: What advice would you give a person who was diagnosed?

Debbie: I don't really feel that I can give any specific advice because each case is different. However, I would suggest that the person say a lot of prayers and be hopeful. It’s a very personal thing, so each person must cope with the situation in a personal way that is effective for them.



Group: Do you think anything positive resulted from the experience?

Debbie: Of course. Now I appreciate each day and myself more. There's a level of seeing things each day as a gift and realizing that every day is not guaranteed.



Group: What would you have to say about the doctors with whom you dealt and the care you received?

Debbie: I was grateful to the doctor because he did his own testing. Had he not conducted his own testing there, and instead referred me to another doctor, I feel it was highly likely that I would have put off getting an ultrasound, and potentially had a worse outcome. He called me about 6 p.m. to try to get me to schedule a surgery appointment as soon as possible; he was a little emotional himself because of the emphasis on cancer . The surgeon was excellent. He listened to me and my husband's requests and had answers because of his experience. He was patient even though he was very busy. He came every day in the hospital to visit.



Group: How do you feel about the work of cancer organizations?

Debbie: Based on what I read on saw tv I realized that there are kind organizations out there. I personally did not deal with any of these organizations, but now I realize more so than before that it is important to support these organizations. I firmly believe that my situation may have been worse if not for research that was at least partially funded by these groups. I would suggest to anyone looking for a way to help people in need to think about donating time or money to a cancer awareness organization.

Post #1 Introduction to Project

This blog is being maintained by a group of three students at Rockhurst University in Kansas City, MO. The project is centered around a service learning effort in which we will be downloading and running a program in order to contribute to the efforts of a grid-computing project. Grid-computing is the linkage of many individual PCs to form a large and computationally powerful network capable of processing information much faster than could be done in a lab. In particular, our group will be working with the Folding@home distributed computing project. Even more specifically our group will focus on the efforts of furthering the knowledge on cancer as a disease.


Folding@home started on October 1st 2000, and is one of the older protein simulation projects . At last count the team had published 45 papers. The Folding@home team started by simulating proteins such as an alpha helix and has since moved to things such as HIV and beta-beta-alpha folds. The predicted folding times for these proteins were close to the actual folding times, and after testing the team was confident that their algorithim was on the right track. The team has since proceeded to computational drug research, studies on cancerous tumor supressors, and work on the folding of proteins and pepetides in small spaces. Their current and completed projects deal with Alzheimer's disease, cancer, Huntington's disease, Osteogenesis Imperfecta, Parkinson's Disease, and ribosome and antibiotics. The project currently has 200,000 active CPUs and can be run on Linux, Mac OS X, Windows, and Playstation 3.


As mentioned earlier this blog will focus on the cancer aspect of the project and future posts will be more topic specific to that area. If you are intersted in joining the Folding@home project you can learn about and download the program at http://folding.standford.edu/ .


For a list of other grid-computing projects visit http://www.volunteerathome.com/sections/active_projects/active_projects.htm